Without limiting the scope of the invention, its background is described in connection with treating and enhancing fracture repair and bone formation.
The skeleton provides a number of functions, such as the provision of support, the protection of internal organs and the provision of sites for the attachment of muscles and tendons which operatively function to enable an animal to move. Bone is a living tissue which is being constantly resorbed, replaced and remodeled during growth and development. This is particularly relevant during skeleton development and fracture repair. When the adult skeleton is formed it requires constant maintenance to ensure its functions are adequately maintained.
The deposition, resorption and/or remodeling of bone tissue is undertaken by specialized, anabolic cells known as osteoblasts (involved in bone tissue deposition) and resorptive cells, known as osteoclasts (involved in the resorption of bone tissue). Osteocytes produce a number of factors that influence bone formation and resorption. The activity of these specialized cells varies during growth and development. During normal, early human development, new bone tissue is formed faster than old bone is resorbed, resulting in bone becoming larger, heavier and more dense. In the fully developed human adult, peak bone density mass is achieved during the late 20's. However, in later life, osteoclast activity exceeds that of osteoblasts, resulting in a decrease in bone density and, consequently, a reduction in bone mass.
Bone loss results in demineralizing disorders such as osteoporosis and enhances the susceptibility to fractures that are responsible for significant morbidity, mortality and excess health care costs. With the anticipated aging of the U.S. population, admissions for fractures are anticipated to rise with attendant costs of $25 billion per year by 2025. New strategies aimed at increasing bone mass are needed to address the significant costs and co-morbidities associated with osteoporosis and fractures, particularly in the aging population.
U.S. Patent Application Publication No. 2005/0101673, entitled, “Use of Orally Available Prostacyclin Derivatives for the Production of a Pharmaceutical Agent for Treating Diseases that are Associated with Bone Marrow Edemas,” discloses the use of orally available prostacyclin derivatives for the production of a pharmaceutical agent for treating diseases that are associated with bone marrow edemas.
U.S. Patent Application Publication No. 2003/0139372, and U.S. Patent Application Publication No. 2004/0171692 both entitled, “Modulation of Bone Formation” discloses the use of an activator or ligand of a peroxisome proliferator-activated receptor, other than PPARγ, or pharmaceutically acceptable derivative of said activator or ligand, in the manufacture of a medicament for the treatment or prophylaxis of bone disease allows, for the first time, bone anabolism to enhance the deposition of bone in conditions which would benefit from increased bone deposition. The reverse, where there is inhibition and/or retardation of bone deposition is also facilitated.
U.S. Pat. No. 8,580,800, entitled “1,4-diaryl-pyrimidopyridazine-2,5-diones and their use” discloses 1,4-diarylpyrimido[4,5-d]pyridazine-2,5-dione derivatives for the treatment and/or prevention of diseases and also to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of disorders of the lung and the cardiovascular system.